Divergent Side-Chain Networks of the Mineralocorticoid Receptor Control Mutation-Altered Drug Response

The mineralocorticoid receptor (MR) is a nuclear hormone receptor whose activation depends on ligand-induced conformational changes of the activation function-2, particularly involving helix 12. The rare gain-of-function mutation S810L was reported to alter MR pharmacology by converting classical steroidal antagonists such as spironolactone or eplerenone into agonists. In contrast, the non-steroidal antagonist finerenone has been shown to retain its functionality. However, the mechanistic reason for those ligand-specific effects remains elusive. To uncover the molecular basis for this ligand-specific behavior, we performed molecular dynamics simulations of wild-type and S810L MR bound to eplerenone or finerenone. We combined distance metrics with a residue-centered dynophore analysis and MDPath to track allosteric communication pathways and time-resolved side-chain interactions. In S810L, eplerenone shifts AF-2 side-chain networks toward H12, consistent with an agonist-like topology. Finerenone, by contrast, induces a local H3-H5 compaction around M777-810 yet diverts the AF-2 network away from H12, thereby preserving an antagonist-like topology. These network reallocations are absent in wild-type simulations, indicating a mutation-specific ligand-depending divergence. Together, these findings provide a mechanistic explanation for ligand-specific antagonist resilience in S810L MR and represent an example for structural pharmacogenomic approaches.